The purpose of this project is to examine the role of the monocyte-macrophage system and related cells in the bone resportion process. Local bone remodeling is influenced by interactions which occur between bone cells, the bone microenvironment, monocytes and lymphocytes. In vitro systems will be used to study the factors involved in the differentiation or activation of osteoclasts. Recently, we have found that highly purified or recombinant lymphokines and monokines are capable of stimulating osteoclastic bone resportion in vitro. These cytokines which stimulate bone resorption (lymphotoxin, tumor necrosis factor and interleukin-1) and another lymphokine which inhibits bone resorption (gamma interferon) will be studied and their effects on bones in organ culture fully characterized. We will evaluate the effects of gamma interferon on osteoclastic bone resorption stimulated by the OAFS since this lymphokine appears to specifically inhibit bone resorption stimulated by these factors. We will clarify the relationships between these cytoklines and the activity formerly referred to as osteoclast activating factor using monoclonal and polyclonal antibodies to the cytokines which block their biological effects on bone. We will assess the effects of recombinant lymphotoxin and tumor necrosis factor on calcium homeostasis in vivo using intact and parathyroidectomized rats. We will evaluate the effects of these recombinant cytokines on osteoclast progenitor cells using the modified Dexter marrow culture system in which osteoclast-like cells form in vitro. We will assess the effects of these cytokines on bone formation in vitro using organ cultures of fetal rat calvaria. It is our contention that studies on these local factors which are produced in the bone microenvironment will be necessary for our understanding of the local factors which normally control trabecular bone volume and normal bone remodeling.